Health Science Center, School of Pharmacy, Xi'an Jiaotong University, 76# Yanta West Road, Xi'an, 710061, China.
J Mater Chem B. 2021 Jan 28;9(3):683-693. doi: 10.1039/d0tb02661a.
Most small-molecule drugs influence cell behavior through their interaction with one or more cellular proteins. The efficacy is unanticipated in the later stages of drug development if small-molecule drugs are discovered in the absence of a biological context. Bionic screening is an in vivo drug-receptor interaction platform that can identify small molecules with recognized activity, improving the likelihood of drug efficacy in the clinic. Here, we report the design of an innovative cell-based bionic screening system using 3D microcarrier cultures to simulate in vivo conditions and facilitate small-molecule drug discovery. Through its combination with HPLC/MS, the method can comprehensively identify small-molecule lead compounds in arbitrarily complex systems in an unbiased manner. In particular, cell-covered microcarriers provide a high-density of cells for affinity performance assessments in the absence of appreciable cell damage and maintain immunogenicity, the 3D structure of which is similar to tissue morphology in vivo, thereby mimicking in vivo drug-receptor interactions. The method is scalable, easy to handle, and requires minimal optimization across a range of different cell lines to realize high-throughput drug screening for the corresponding diseases. This provides a valuable tool for lead compound discovery in more physiologically relevant systems and may address the lack of clinically available drugs.
大多数小分子药物通过与一个或多个细胞蛋白相互作用来影响细胞行为。如果在没有生物背景的情况下发现小分子药物，那么在药物开发的后期，其疗效是无法预料的。仿生筛选是一种体内药物-受体相互作用平台，可以识别具有公认活性的小分子，提高药物在临床上的疗效。在这里，我们报告了一种创新的基于细胞的仿生筛选系统的设计，该系统使用 3D 微载体培养来模拟体内条件，并促进小分子药物的发现。通过与 HPLC/MS 的结合，该方法可以在不造成明显细胞损伤的情况下，以无偏倚的方式全面鉴定任意复杂体系中的小分子先导化合物，并保持其免疫原性。细胞覆盖的微载体为亲和力性能评估提供了高密度的细胞，而 3D 结构与体内组织形态相似，从而模拟体内药物-受体相互作用。该方法具有可扩展性，易于操作，并且在不同的细胞系中需要最小的优化即可实现相应疾病的高通量药物筛选。这为在更接近生理的系统中发现先导化合物提供了有价值的工具，并可能解决临床上缺乏可用药物的问题。
